Substituted benzo-1,4-oxazines



United States Patent US. Cl. 260244 12 Claims ABSTRACT OF THE DISCLOSURE N-substituted 3 ,4-dihydro-(2H) -l,4-benzoxazines useful as analgesics which possess relative freedom from undesirable side effects, such as depression of the respiratory system and dilation of the pupils of the eyes. Several representative examples of the compounds are 4-(piperidinoacetyl)-3,4-dihydro-(2H) 1,4 benzoxazine and 4-(dimethylamino-acetyl)-3,4-dihydro (2H) 1,4 benzoxazine.

This invention deals with N-haloacylated 3,4-dihydro- (2H)-1,4-benzoxazines, methods for their manufacture, and pharmaceutical compositions as well as methods of applications thereof for producing analgesia. The compounds possess advantageous properties; they are useful drugs, in particular analgesics having beneficial freedom of undesirable side effects. The invention also deals with other novel precursors and derivatives of said N-haloacylated benzo-1,4-oxazines.

This invention is concerned with a new N-substituted benzo-1,4 oxazine of the Formula I wherein R is selected from one of the following: hydrogen, chlorine, methyl or methoxy, R R and R are each selected from one of the following: hydrogen, alkyl of 1 to 3 carbon atoms, phenyl or benzyl, R and R are each, when considered individually, selected from one of the following: hydrogen, alkylof 1 to 6 carbon atoms or cycloalkyl-radical of 3 t0 6 carbon atoms, alkyl substituted phenyl, said alkyl being a lower alkyl group, in which the phenyl might be substituted by one or a plurality of methoxy groups, and R and R are, considered together with the adjacent nitrogen atom, a heterocyclic ring selected from the following: piperidino, pyrrolidyl, morpholino and N'-methylpyrazinyl, and A is 3,547,915 Patented Dec. 15, 1970 "ice alkylene of l to 3 carbon atoms, or their non-toxic, pharmaceutically acceptable acid addition salts.

The compounds have a combination of useful and unexpected pharmacological properties without undesirable side effects. The N-aminoalkyl-(2H)-l,4-benzoxazines-3- (4H)-one (phenmorpholone-li) disclosed by Kurihara et al., in Tohoku Yakka Daigaku Kiyo, 9, 77-81 (1962), CA. 59, 2808b (1963) are distinctly different from the compounds of the invention.

The new compounds of the invention may be prepared by the following methods which have been found particularly advantageous. Reaction of an N-haloacylated 3,4-dihydro-(2H)-l,4-benzoxazine of the Formula II.

wherein Hal represents, for instance, chlorine or bromine with an amine of the Formula III R (III) wherein R and R have the definition stated above. The reaction is carried out preferably in the presence of an agent which neutralizes the generated hydrogen halide. The reaction is advantageously carried out by reacting equimolar quantities of the individual reaction components. Suitable agents for neutralizing the hydrogen halide are, for example, triethylamine or a dialkyl-aniline and the like. Instead of a separate agent capable of neutralizing the hydrogen halide, two to three mols of the amine, i.e. one of two mols excess, may also be employed. The reaction is carried out in the presence or absence of a solvent, such as an alcohol, especially ethanol, or hydrocarbons, especially benzene or toluene, etc. at temperatures between about room temperature and the boiling point of the solvent used, such as or between 20 and 200 C., preferably between 80 and C.

The production of the above described haloacylated compounds II may be accomplished by reacting the corresponding 3,4-dihydro-(2H)-1,4-benzoxazine, with a haloacylated halogenide like Hal--A-CO-Hal, wherein A has been defined above.

The non-toxic, pharmacologically acceptable, addition salts of the compounds of the invention are readily obtainable by classical methods to give the hydrochloric, sulfuric, phosphoric, acetic, maleic, sulfonic, tartaric, ascorbic acid salts, respectively, and the like.

The compounds of the invention are useful drugs. They have a useful and unobvious combination of pharmaceutical properties, particularly they possess excellent analgesic activity free of undesirable side effects. In particular, they exhibit fredom of depression of the respiratory systems in mammals. They also are free of dilating effect on the pupils of the eye. In this respect, the compounds of the invention offer unexpected advantages over morphine and its known narcotic derivatives which are known to have undesirable depressive inhibition on the respiratory center systems. The compounds of the invention are therefore a highly useful group of drugs.

The following examples are further illustrative of the invention and are not to be construed as a limitation thereof.

EXAMPLE I 4 (dimethylamino-acetyl)-3,4-dihydro (2H) -1,4- benzoxazine is prepared as follows.

In a solution of grams of dimethylamine in 100 m1. of benzene, there are added portionwise 21.2 grams of 4- (chloroacetyl -3 ,4-dihydro-(2H)-1,4-benzoxazine while cooling and stirring. The reaction mixture is allowed to stand 24 hours at room temperature, the benzene solution is sucked off from the separated dimet-hylamine hydrochloride; and the liquid phase is extracted several times with dilute hydrochloric acid. From the collected acid portions, the base is precipitated by the addition of dilute sodium hydroxide and is taken up in ether. After drying over potassium carbonate, the solvent is distilled off and the product which is obtained by recrystallization from cyclohexane amounts to 20.5 grams (93% of theory) and melts at 6364 C.

The 4-chloroacetyl-3,4-dihydro-(2H)-1,4-benzoxazine used above (having a melting point of l08l09 C. upon 4 EXAMPLE 2 In a similar manner as in Example 1, there is obtained 4-(methylamino-acetyl)-3,4-dihydro (2H) 1,4-benzoxazinc from the reaction of 4-chloroacety'l- 3,4-dihydro- (2H)-1,4-benzoxazine with methylamine. The product has a boiling point of 139l4l C./0.4 mm. Hg; the hydrochloride has a melting point of 208-209 0, upon recrystallization from ethanol.

EXAMPLE 3 The 4-(piperidino-acetyl)-3,4-dihydro (2H) 1,4- benzoxazine is prepared as follows.

There are heated 21.2 grams of 4-chloroacetyl-3,4-dihydro-(2H)-l,4-benzoxazine under reflux for 2 hours with a solution of 19 grams of piperidine in 100 ml. of henzene. After cooling, the benzene solution is sucked off from the precipitated piperidine hydrochloride, and then extracted several times with hydrochloric acid. From the acid extracts, the base is precipitated by addition of dilute sodium hydroxide and then taken up in ether. After drying over potassium carbonate, the solvent is distilled off. There is obtained 23 grams of the base (89% of theory); the product has a boiling point of 138140 -C./ 0.01 mm. Hg; melting point 6870 C.; the hydrochloride has a melting point of 216 C., upon recrystallization from ethanol.

EXAMPLES 4-16 In Table I, below, there are given the starting 4-haloacylated-3,4-dihydro-(2H)-1,4-benzoxazines, of the general Formula II, given above, which are reacted with the respective amines III to give the new compounds, listed below in Table 11, having the general Formula I.

TABLE L-EXAMPLES 4-16 [Typical 4-haloaeylated-3,4-dihydro-(2H)-1,4-benzoxazine] Examples R1 R1 R R A Hal. M.P. or .P., C

(CHzh Cl 1 108-11 (CH2): Cl -51 CH(CH Br 2 130-131 CH2 Cl 101-102 CH2 01 92-93 CH2 Cl 81-82 CH2 Cl 105-106 CH2 Cl 91-92 CH2 CI 56-57 CH1 C1 1 148-150 C H2 Cl 100-101 15 H H H CH3 CH2 CI 89-90 16 H H H CH2 Cl 133-134 At; 0.1 mm. Hg. 2 At 0.2 mm. Hg.

recrystallization from ethanol), is obtained by the reaction of 3,4-dihydro-(2H) 1,4-benzoxazine with chloroacetyl chloride.

Following the procedure of the examples above, there are prepared the compounds of the invention, as illustrated in Table II.

HOHH N w m N6 w mmumm iouif. m HQ O m m m m I. 3 s32 17% 27 m l i m m m m 1. HwH omH m H m mwm Hm m :8...: m m 56L 0w AEOQQmmvawm HH SMO 1::||||||||\-|:.wEmw

. 5 8 w I m m "mo gi E0 0 50 m m m 823 m m m $72: m m m $28 m m m l l I l I l |||||l|| Al rl ll:

- E k qmovmo .4 t I l m m m 1]\ 37%: :aqsm 2 m m m $32 a 259 mo mo m m m 315 A l m m m s72: 258 mo 50 m m m 532 io z Z m m m /I\ o z m m m 5 a s mo m m m imam m m m m ig :iiaqaw A m v m m m m $15 N $32 mo E6 mG i m m 6 av 22 8 0V 5 mm 4 E E Q m m EXAMPLE 42 The 4-(amino-acetyl)-3,4-dihydro-,(2H)-1,4 benzoxazine is prepared by adding to a solution of 13.5 grams of 3,4-dihydro-(2H)-1,4-benzoxazine and 11 grams of tri- 8 subcutaneous and oral administration. The analgesic effeet is determined by the hot plate method, Chen. J.Y.P., H. Beckmann, Science 113, 631 (1951), and the electroshock method, Luckner and Magun, Journ. Exp. Med. 117, 133 (1951). The antipyretic effect was determined after of a sequently the mixture is heated under reflux for one hour. mometer. the rectal temperature of a normothermlFal rat The liquid fraction is sucked off from the precipitate was Continuously .measured' i effect on the.res.plratory which is stirred with water, the liquid fraction is sucked a i g l :fter mtrafenous i gi f off again and washed with water. After recrystallization i i morp 8 OW a respiratory m 1 won 8 ect from dimethyl formamide there are obtained 24 grams whlch amzlgomzed by levanorphan new compound of 4 (phthalimido acetyl) 3 4 dihydro (2H) 1 4 hem of the invention do not effect the respiratory system. Zoxazine having a meltin point of 2224235 C It 1 s evident that the new compounds are useful drugs 23 5 grams of the 4-( phthalimido-acetyD-3 4-dihyd especlally valuable analgesics because unlike morphine, 4 benzoxazine are reduced to a fine pwder codeine and like narcotics, they do notparalyse the respirapended in 250 ml of ethanol and then heated while stirnon centre E not lead to addlctlon' In additlon they ring under reflux to boiling. During one hour there are do i :mnpyrenc efiects wPParable Wlth known added dropwise 4.8 grams of an 80% hydrazine solution 52 gi 2 9? "i l i g q g f b in 50 ml. of ethanol, subsequently, the mixture is again fi m y e a mi ere 1S Osage orm y means of dlverse compositions, such as tablets, sugarheated for 4 hours to bollmg. The cooled solution is sepa rated by suction from the precipitated phthalyl hydrazide, Rated P 1115 capsules ampoules supposltones drops or the concentrated to about 50 ml. and there is obtained by 1 filtration of the resulting precipitate, upon the addition of g tablet Columns the followmg mgrqdlems alcoholic hydrochloric acid, the 4-(amino-acetyl)-3,4- i e preparatlon of 10,000 tablets) and 15 P dihydro-(ZH)-1,4-benzoxazine hydrochloride. Upon re- 29 pa 6 as 0 Grams crystallization from ethanol, there are obtained 13 grams of hydrochloride having a melting point of 256258 c. gi l t 55 igg 288 The N-amino-acyl-3,4-dihydro-(2H)-1,4-benzoxazines, a 1 a er c n en prepared in the above examples, are excellent analgesics lpyrro 1 2333 q g which are free of the undesirable depressive inhibition on 30 ymel' 3/ weig th respiratory system, The ingredients are mixed with ethanol or isopropanol The following is an evaluation of typical compounds to give an evenly granulated mass (1.2 mm. particle size). f the i ti The material is dried to 870 grams and then screened to TABLE III a particle size of 1.5 mm. and admixed with Grams Compound evaluation Corn starch 105 Designation: Compound Talcllm ""5,- 20 1 4 (piperidino-acetyl)-3,4-dihydro-(2H)- Calcmm am mate 5 1,4-benzoxazine. Tablets of 100 mg. each are pressed from 1 kg. lots. The 2 4-(dimethylamino-acetyl) 3,4 dlhydrotablet contains 30 mg. of active and 100 mg. of carrier (2H)-1,4-benzoxazine. substance, respectively. 3 2 isopropyl-4-(pipe idi oy Dragees are prepared in a similar manner from 30 mg. hydro-(2H)-1,4-benzoxazine. and 50 mg. of active and carrier substance and coated 4 2 ph v -(p p y )-3, 1 ywith sufficient sweetening material to a total weight of dro-(2H)-1,4-benzoxazine. about 115 mg. 5 7 methoxy-4-(N-dimethyl-acetyl)-3,4-di- Ampoules (1 ml.) contain the following:

hydro-(2H)-1,4-benzoxazine. 6 6-chloro-4-(piperidino-acetyl) 3,4 dihyoffhe dmflH)'l4'benmazine' ififii filiiiliilfiifiif ii 0-0 01 ml 7 6 methyl-4-(piperidino-acetyl)-3,4-dihydest 8 i ggggf 'igif Sterilization-45 minutes at 101 0. 9 Ph The amount of the effective material of the invention 10 Codeine, whlch would normally be administered is primarily de- TABLE IV.EVALUATION OF COMPOUNDS Analgesic efieet Effect on body Acute toxicity temperature LD50 (mg/kg.) Hot plate Electro-shOck normottherilnlcal ra ora Sub- Sub- Subdose mg./kg. euta- Oral cuta- Oral euta Oral neous dose neous dose neous dose 50 100 150 220 15 5. 5 30 -0. 5 -1. 5 450 550 50 95 45 50 -0. s -1. 7 330 500 15 35 -0. 6 0. 1 410 450 45 so -0. 4 0. 5 300 450 220 200 1.5 105 215 12 35 s 760 50 100 9 890 200 l Only intraplanatar dose.

The compounds were further shown to be free of dilating effect on the pupil of the eye, in contrast to codeine.

Methods of testing.

The acute toxicity is determined by the method of Litchfield and Wilcoxon on white mice by intraveneous,

termined by the physical characteristics of the recipient, and severity of the case. Obviously, the amount of the particular compound to be administered must be an effective amount, i.e. an amount which is medically beneficial. It would be expected that the adult human dosage wherein R is selected from one of the following: hydrogen,

chlorine, methyl or methoxy,

R R and R are each selected from one of the following: hydrogen, alkyl of l to 3 carbon atoms, phenyl or benzyl,

R and R are each, when considered individually, se-

lected from one of the following: hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,

R and R are, when considered together with the adjacent nitrogen atom, a heterocyclic ring selected 5 from one of the following: piperidino, pyrrolidyl, morpholino and N'-methyl-pyrazinyl, and

A is alkylene of 1 to 3 carbon atoms or their non-toxic,

pharmaceutically acceptable acid addition salts.

2. A benzo-1,4-oxazine of claim 1 in which R and R are, when considered together with the adjacent nitrogen atoms, a heterocyclic ring selected from one of the following: piperidino, pyrrolidyl, morpholino and N'- 3. A benzo-l,4-oxazine of Claim 1 in which R and R are both alkyl or their non-toxic, pharmaceutically acceptable acid addition salts.

4. A benzo-1,4-oxazine of claim 1 in which R and R are selected from hydrogen, phenyl and alkyl or their non-toxic, pharmacentically acceptable acid addition salts.

5. A non-toxic, pharmaceutically acceptable acid addition salt of a com ound of claim 1.

6. 4-(piperidino-acetyl) 3,4-dihydro-(2H)-1,4-benzoxazine.

7. 4-(dimethylaminoacetyl) benzoxazine.

8. 2-is0propyl-4-(piperidino acetyl)-(2H)'3,4-dihydro-l,4-benzoxazine.

9. 2-phenyl-4-(piperidino-acetyl) (2H)-3,4-dihydro- 1,4-benzoxazine.

1t 7-methoxy-4-(N-dimethyl (2H l ,4-benzoxazine.

11. 6-chloro-4-(piperidino-acetyl) 3,4-dihydro-(2H)- 1,4-benzoxazine.

12. 6-methyl-4-(piperidino acetyl)-3,4-dihydro-(2H)- 1,4-benzoxazine.

- 3,4-dihydro-(2H)-1,4

acetyl)-3,4-dihydro- References Cited UNITED STATES PATENTS 4/1945 Dickey et al 260244 10/1962 Berg 260-244 OTHER REFERENCES NATALIE TROUSOF, Primary Examiner US. Cl. X.R. 

